Monocytes and macrophages express CD4 on their surface, are targets for HIV-1, and may serve as a reservoir or the virus. Ongoing studies focus on the role this population plays in the progression of HIV-1 disease and as targets for antiviral therapy. Human saliva contains potent anti-HIV-1 factor(s), consistent with the lack of spread of HIV-1 by the oral route. Infection of adherent primary monocytes with HIV-1 is dramatically suppressed in the presence of human saliva. Secretory leukocyte protease inhibitor (SLPI) was found to contribute the major portion of this antiviral activity. SLPI has potent anti-HIV-1 activity with an approximate IC90 of 1 microgram/ml in monocytes. SLPI is produced in the major and minor salivary glands and in other mucous producing cells of the body, but not in circulating blood cells (by current detection methods) nor in the pancreas. Additionally, SLPI is present in equivalent amounts in both healthy and HIV infected individuals. The presence of SLPI in the oral cavity may be critical in the prevention of free virus infection of leukocytes found in the crevicular spaces and elsewhere in the oral cavity, thus reducing the chance of infection through the oral route. SLPI inhibits infection through interaction with the host cells. SLPI does not bind to CD4 or prevent HIV from interference with an early step of virus infection, i.e. viral entry. SLPI binds with high affinity to monocytes, to a single class of receptor sites (about 7000 receptors per monocyte) with a Kd of 3.6 nM. The putative SLPI receptor was identified as a surface protein with molecular weight 58-60 kD. Recombinant SLPI variants mutated at position 72, thereby modifying antiprotease activity, still bind tightly to monocytes and retain anti-HIV-1 activity, therefore the antiprotease function of SLPI may be distinct from its anti-HIV-1 activity. The unique antiviral activity of SLPI may make it a key factor in our understanding of the early steps of HIV-1 infection of monocytes.